Musculoskeletal Disorders and Bone Defects.
Musculoskeletal disorders and bone deficiencies have been established as among the most important human health concerns, costing society an estimated $254 billion annually, and afflicting, for example, 1 out of 7 Americans. Such conditions are prevalent in the aged population, and the number of individuals presenting with a bone deficiency is anticipated to increase as the population ages (the number of people over age 50 will double between 1990 and 2020). Bone defects are frequently caused by trauma, disease, developmental deformity, and tumor removal.
Need for Improved Treatment Methodology.
There is a critical need for improved treatment methodology for bone disorders (Ducheyne, 1999). Currently, repairing such bone sites involves various medical surgical techniques, including the use of autogenous grafts, allogenous grafts, internal and external fixation devices, electrical stimulation, and replacement implants. Although effective in many cases, such existing technologies have numerous difficulties and disadvantages. Moreover, current cell culture methods for tissue-engineered bone grafting materials produce weakly organized sheets of cells, and these constructs cannot withstand the mechanical forces present in vivo (Vandenburgh, 1991).
Need for Improved Bone Grafting Material.
Currently the gold standard for the hone reconstruction and guided bone regeneration (GBR) applications is the autogeneous bone graft (e.g., Yaszemski, 1996; Buser, 1994), and the use of biodegradable bone substitute would be desirable in such applications to avoid the second site surgery for autograft harvesting. There is therefore a pronounced need for a material that can be implanted into individuals to restore their lost structure and function, and particularly a need for a bone grafting material that will permit rapid cell growth and maturation within, while providing the initial biomechanical support required for ambulatory function. This material must accomplish this objective while slowly transferring this function to the developing tissue (Burg, 2000). Lack of such a material prevents clinical applications to provide immediate restoration of functional load bearing (Lanza, 1997).
Bioresorption and Tissue Restoration; Use of Calcium Phosphate Bioresorbable Ceramics.
Although fabrication of high-strength materials which can replace lost tissue function temporarily is known in the art, the ideal material for permanent implant application must be capable of not merely replacing tissue function, but of restoring lost tissues. Therefore, such an ideal material be bioresorbable to allow the native tissues to gradually replace the implanted material with host hone. Although calcium phosphate bioresorbable ceramics are known in the art, little work has been reported on improving mechanical properties of these materials for hard tissue engineering applications. Three factors that cause in vivo resorption of calcium phosphate bioceramics are: (i) physiologic dissolution, which depends on pII and composition of calcium phosphate; (ii) physical disintegration, which may be due to biochemical attack at the grain boundaries or due to high porosity; and (iii) biological factors such as phagocytosis.
Individualized Applications and the Lack of Adequate Resorbable Materials.
As shown in TABLE 1 below, the mechanical properties of bone depend substantially upon their physiologic function, and the desired rate of biodegradation of synthetic materials will ideally depend on the application site and the particular patients needs. For example, in craniomaxillofacial applications such as localized ridge augmentation, a relatively rapid biodegradation is desirable, particularly prior to dental implant placement because new bone should ideally form while leaving no residual particles to interfere with preparation of the implant bed at the time of surgery (Yaszemski, 1996). By contrast, for spinal grafting, a slow biodegradation and strength loss is desirable until new bone grows. Bioactive calcium phosphate ceramics and bioactive glasses have recently been considered as candidate biomaterials for craniomaxillofacial applications. However, for β-tri calcium phosphate (β-TCP), the biodegradation has been reported to be incomplete even after 9.5 months after grafting in the human mandible, and histological examination of these biopsies revealed that 34% of the biopsy consisted of mineralized bone tissue and 29% of remaining β-TCP (Zerbo 2001). Likewise, in the case of bioglass 45S5, the particles have been reported to resorb over 1-2 years, by dissolution rather than osteoclastic activities (Tadjoedin 2002). Moreover, currently, there is no ideal synthetic material for spinal grafting applications. Such examples illustrate the need for development of biodegradable ceramic materials that will act as a scaffold and support bone remodeling in an time frame appropriate to the particular application. Ideally, such desired materials should degrade in a controlled fashion into non-toxic products that the body can metabolize or excrete via normal physiological mechanisms (Yaszemski 1996).
TABLE 1Properties of Human Bone (Yamada, 1970).Modulus ofTensileCompressiveelasticityStrengthStrengthTissueDirection(GPa)(MPa)(MPa)FemurLongitudinal17.2121167TibiaLongitudinal18.1140159FibulaLongitudinal18.6146123HumerusLongitudinal17.2130132RadiusLongitudinal18.6149114UlnaLongitudinal18.0148117Cervical VertebraeLongitudinal0.233.110Lumbar VertebraeLongitudinal0.163.75Spongy Bone0.091.21.9SkullTangential—25—SkullRadial——97
Extracellular Matrix Composition of Bone; Presence of Trace Elements.
The composition of the extracellular matrix of human bone is well known, comprising: approximately 69 wt % substituted carbonate-hydroxylapatite mineral; 22 wt % organic substances; and 9 wt % water (e.g., LeGeros, 1990; Suchanek, 1998; Park, 1984). Apart from Ca and P ions, the extracellular matrix also comprises Na+, Mg2+, K+, CO32−, F−, Cl−, and trace amounts of Zn2+, Fe3+, Cu2+, Pb2+ and Sr2+. Typical crystallite sizes are in the range of 25 nm thick (40-120 nm wide and 0.16 to 1 micron long), and the ‘ignition’ product results in hydroxyapatite (HAp), CaO and β-TCP phases (LeGeros, 1991). The Ca to P ratio varies in hone, enamel and dentine, where hone has the highest Ca (1.71:1 of Ca:P), and dentine has the lowest (1.61:1 of Ca:P) (Suchanek, 1998). A small change in chemical composition in CaP based ceramics has been shown to significantly alter sintering characteristics and related properties. Adding small amounts of metal ions to these materials can also alter their mechanical and biological properties. Such trace elements effect overall performance of human bone, and it is thus important to incorporate these them in to implants because the biocompatibility of ‘apatites’ is closely dependent on their composition (Knowles, 1996).
Sodium (Na) and fluorine (F) ions are both found to occur naturally in human bone tissue. The extent to which Na and F are substituted in an apatite-based dental restoration will likely affect apatite solubility and the ability of the restoration to resist further acidic challenges. The addition of sodium to calcium phosphate ceramics has been reported to induce the formation of other phases such as β—Na2CaP2O7 and Na3Ca6(PO4)5. These phases are known to have high bioresorbability and degradation rates in physiological media. Fluorine is also a common ion in human bone tissue, but is found in particularly higher concentrations in tooth enamel. The presence of fluorine in calcium phosphates can result in formation of fluorapatite (FAP) Ca10(PO4)6F2. Studies have indicated that fluorine can promote bone regeneration and also lead to lower solubility/degradation of calcium phosphate ceramics due to its acid resistivity.
Calcium oxide (CaO) is a naturally existing phase in bone tissue. The addition of CaO will increase the calcium to phosphorous ratio in the TCP (Ca3(PO4)2), which plays a significant role in the degradation rate of particular calcium phosphate ceramics. Moreove, Kalita et al. found the compression strength of HAP to increase when CaO was supplemented as a sintering additive.
Resorption of Bone Materials and Calcium Phosphate Bioceramics.
Calcium phosphate (CaP) ceramics are considered among the most promising materials for bone tissue engineering because of their bone-like composition and mechanical properties. Hydroxyapatite and tricalcium phosphate are used in orthopedic, maxillofacial, and dental implant surgery either as a temporary support scaffold or in a particulate paste to fill bone defects. Biodegradation properties of these materials allows for bone tissue engineering applications, because they can promote apatite formation and simultaneously deliver growth factors for osteoinduction. Significantly, however, the process of resorption of calcium phosphate bioceramics is quite different from that for bone, essentially because of different textures. Bone mineral crystals possess a very large surface area because they have grown in an organic matrix and have very loose crystal-to-crystal bonds, resulting in a relatively homogeneous resorption by osteoclasts. By contrast, calcium phosphate bioceramics present a low surface area and have strong crystal-to-crystal bonds. Resorption takes place in two steps: the disintegration of the particles into crystals, and the dissolution of the crystals (Heughebaert, 1988).
Use of Tricalcium Phosphate (TCP; Ca3(PO4)2).
Tricalcium phosphate (TCP; Ca3(PO4)2) is a CaP based synthetic material that forms a bioactive bond with natural bone. Compared with hydroxyapatite, TCP has a lower calcium-to-phosphorous ratio, which increases the degradation rate when the ceramic is placed in a biological environment. TCP degrades in the body and the products are resorbed by the surrounding tissue. Therefore, such matrix absorption may be used to expose surfaces to tissue or to release admixed materials such as antibiotics or growth factors in controlled drug release. Among several clinical applications of TCP, two that are currently being researched are posterior spinal fusion and dental augmentation. Improving mechanical properties, bioactivity, and osteoconduction might also trigger faster bone in-growth in dental applications.
In summary, therefore, mechanical properties of particular hones depend substantially upon their respective physiologic functions, and optimally the rate of biodegradation of synthetic materials used in particular hone replacement applications should reflect the respective application site and patients needs. For particular applications (e.g., craniomaxillofacial), a relatively rapid biodegradation is desirable, whereas a slow biodegradation and strength loss is desirable for other applications (e.g., spinal grafting).
There is, therefore, a pronounced need in the art for further improved CaP based ceramics. There is a pronounced need for individualized applications of bone replacement/restoration materials. There is a pronounced need for bone replacement/restoration materials that can provide for time-varying mechanical properties while allowing for complete dissolution over an appropriate time frame. There is a pronounced need for bone replacement/restoration materials that reduce or eliminate long-term biocompatibility concerns.